For reliable protection against STD transmission, rectal microbicides must be formulated in a way that will deliver the active agent to all the surfaces that are susceptible to infection. These include the entire rectum as well as a large fraction of the colon (due to peristaltic stirring of colonic contents). Colorectal surfaces are columnar epithelia that are mechanically and osmotically fragile, and are highly susceptible to STD transmission. Although continuous mucus secretion by these susceptible surfaces helps protect against trauma and pathogens, this continuously secreted mucus also poses a significant barrier against effective delivery of microbicides to the epithelial surface. Recently we developed novel mucus penetrating nanoparticles (MPP) that can overcome this barrier and provide sustained, well-distributed delivery of drugs to mucosal surfaces. Our hypothesis is that MPP will significantly increase the protective efficacy of rectal microbicides by achieving more uniform and complete colorectal distribution, sustained drug activity, and thus longer duration and more complete protection compared to drug delivered in gels (free drug) or drug delivered in conventional nanoparticles, CP, that adhere to mucus and fail to penetrate mucus barriers. In the R21 phase, we will determine optimal MPP properties for penetration of mouse colorectal mucus, and we will characterize the uniformity of MPP distribution and retention times in the mouse colorectum compared to CP and free drug. We will then prepare drug-loaded biodegradable and biocompatible MPP that provide sustained release of antiviral drugs (valacyclovir for HSV and UC-781 for HIV). We will deliver these MPP in both a rectal enema format and a rectal lubricant gel format since both formats are frequently used for enhancing rectal intercourse. Moreover, an enema may deliver MPP to large regions of the colon unlikely to be reached by a gel. The key milestone for the R21 phase will be development of valacyclovir-MPP and UC-781- MPP that provide more complete and persistent coverage of the rectal epithelial surface, with minimal toxicity, compared to CP formulations or free drug. In the R33 phase, we will extensively test these MPP formulations for safety and protective efficacy in our mouse/HSV rectal model and in the hu-BLT-SCID mouse/HIV model (via a subcontract with Dr. J. Victor Garcia-Martinez at UNC).